Toxicity Problems Associated With Declofenac In Avaian Species And Its Substitute

Material type: BookPublisher: 2010Subject(s): Department of Pharmaoclogy & Toxicology | Phd. thesisDDC classification: 1784,T Dissertation note: A catastrophic decline in vulture populations was first observed in 1996-97 in Keoladeo National Park, Bharatpur, Rajasthan, India. Later, similar situations were reported in many south Asian countries including Pakistan, Nepal and Bangladesh. Now, the International Union for the Conservation of Nature (IUCN) has listed three vulture species i.e. Gyps bengalensis, Gyps indicus and Gyps tenuirostris as 'critically endangered'.
Vultures are natural scavengers and play a key role in keeping the environment clean by consuming carcasses of dead livestock and wildlife. The unconsumed animal carcasses pose a serious threat to both human and animal health because decaying animal carcasses may contaminate groundwater and become a potential source of diseases such as tuberculosis and anthrax for humans and other animals. Also, due to the declines in vulture populations, a rise in the numbers of other scavengers like dogs has been observed. Therefore, the risk of dog bite and transmission of dangerous diseases, including rabies, has also increased. Furthermore, vultures play a vital role in the disposal of human corpses of the followers of the Parsi religion because they place their dead bodies before vultures for disposal rather burial beneath the earth.
In the South Asian region, different communities have different attitudes toward the use of meat and its products. For example, Muslims do not use meat of dead animals, whereas Hindus abstain from cow's meat altogether because of religious bindings. For many centuries, the disposal of such meat has been done by vultures.
The vulture population decline issue was investigated by researchers with the support of various international organizations dedicated to bird conservation in collaboration with regional ornithological societies. Scientists looked into the problem from different angles and considered a variety of reasons of this decline. These included food shortages, losses of habitat, persecution, human disturbances, infectious agents, environmental contaminants, intentional poisoning, and accidental poisoning through food or water. Initially, the outbreak of some infectious disease and/or poisoning appeared to be the most plausible basis of this crisis. Recent studies have ruled out presence of a widespread infection and have focused on some form of poisoning. Now, it is believed that diclofenac, a veterinary drug, was responsible for the huge fatalities in vultures, in part because the onset of the crisis was coincident with the introduction of this drug in veterinary practice.
Diclofenac belongs to a class of drugs called, non-steroidal anti-inflammatory drugs (NSAIDs). Diclofenac served as an effective analgesic (pain killer), antipyretic (reduces fever), and anti-inflammatory (reduces swelling) drug. Initially, this drug was used in human beings for various indications such as arthritis. The use of diclofenac was started in domestic animals in the region a decade ago. It was reported that the presence of diclofenac in the bodies of dead animals that had been treated with this drug shortly before death was harming the vultures feeding on contaminated carcasses (Oaks et al., 2004; Shultz et al., 2004; Swan et al., 2005).
The Department of Pharmacology and Toxicology, at the University of Veterinary and Animal Sciences, Lahore, has been given the task to investigate this problem. A series of experiments was conducted to study the likely causes of this problem and, if possible, find its solution by developing safer and efficacious alternatives to diclofenac for the treatment of animals. For this purpose, a chicken experimental model was developed to study the toxicity of diclofenac and other NSAIDs. These studies have shown that diclofenac produced similar toxic effects and mortalities in broiler chickens as had been reported from studies of diclofenac-poisoned vultures. Later on, therapeutic efficacy studies of safer alternative NSAIDs of diclofenac were conducted in horses, buffaloes.
On the basis of these current studies, it was concluded that diclofenac was toxic to chickens and no significant difference was present in the death rates in bird groups treated with toxic doses of diclofenac via oral and intramuscular routes. Sodium and potassium salts of diclofenac caused comparable casualties in broiler chickens (unpublished study). A number of other NSAIDs were screened for their toxicity profile using the chicken model. This study showed that phenylbutazone, dipyrone, meloxicam, piroxicam and ketoprofen were comparatively safer than diclofenac. However, phenylbutazone and dipyrone may not be appropriate alternatives for diclofenac in food-producing animals because they are known to cause a condition called agranulocytosis in human and animals. Agranulocytosis involves marked reductions in numbers of white blood cells that are responsible for maintaining the body's immunity against various diseases.
To evaluate the efficacy of safer drugs, fever was induced in buffalo calves with Escherichia coli endotoxin (lipopolysaccharide), and the animals were then treated them with ketoprofen, meloxicam orpiroxicam. Although, all three drugs were effective in lowering body temperature, ketoprofen was the most efficient. In another experiment, these drugs were used in the treatment of lameness in horses, and it was concluded that meloxicam was more effective followed by piroxicam and ketoprofen for the treatment of this particular problem.
Based on these observations, it is concluded that ketoprofen, meloxicam and piroxicam may prove quite safe drugs for the scavenging birds and may be used as safe alternatives to diclofenac in veterinary practice. It has been observed during this study that ketoprofen, piroxicam, and meloxicam are less toxic for broiler chickens and may prove better alternates to be used in place of diclofenac in animals. The use of these NSAIDs may be less toxic for scavenger birds. The commercial preparations of ketoprofen and meloxicam for veterinary use are available at least in two south-east Asian countries i.e. Pakistan and India. The prices of these NSAIDs are comparable with those of the veterinary preparations of diclofenac which were previously available in the region. On the basis of results of this study it is concluded that ketoprofen, piroxicam, and meloxicam are effective NSAIDs in domestic animals, hence may replace diclofenac in veterinary practice.

A catastrophic decline in vulture populations was first observed in 1996-97 in Keoladeo National Park, Bharatpur, Rajasthan, India. Later, similar situations were reported in many south Asian countries including Pakistan, Nepal and Bangladesh. Now, the International Union for the Conservation of Nature (IUCN) has listed three vulture species i.e. Gyps bengalensis, Gyps indicus and Gyps tenuirostris as 'critically endangered'.
Vultures are natural scavengers and play a key role in keeping the environment clean by consuming carcasses of dead livestock and wildlife. The unconsumed animal carcasses pose a serious threat to both human and animal health because decaying animal carcasses may contaminate groundwater and become a potential source of diseases such as tuberculosis and anthrax for humans and other animals. Also, due to the declines in vulture populations, a rise in the numbers of other scavengers like dogs has been observed. Therefore, the risk of dog bite and transmission of dangerous diseases, including rabies, has also increased. Furthermore, vultures play a vital role in the disposal of human corpses of the followers of the Parsi religion because they place their dead bodies before vultures for disposal rather burial beneath the earth.
In the South Asian region, different communities have different attitudes toward the use of meat and its products. For example, Muslims do not use meat of dead animals, whereas Hindus abstain from cow's meat altogether because of religious bindings. For many centuries, the disposal of such meat has been done by vultures.
The vulture population decline issue was investigated by researchers with the support of various international organizations dedicated to bird conservation in collaboration with regional ornithological societies. Scientists looked into the problem from different angles and considered a variety of reasons of this decline. These included food shortages, losses of habitat, persecution, human disturbances, infectious agents, environmental contaminants, intentional poisoning, and accidental poisoning through food or water. Initially, the outbreak of some infectious disease and/or poisoning appeared to be the most plausible basis of this crisis. Recent studies have ruled out presence of a widespread infection and have focused on some form of poisoning. Now, it is believed that diclofenac, a veterinary drug, was responsible for the huge fatalities in vultures, in part because the onset of the crisis was coincident with the introduction of this drug in veterinary practice.
Diclofenac belongs to a class of drugs called, non-steroidal anti-inflammatory drugs (NSAIDs). Diclofenac served as an effective analgesic (pain killer), antipyretic (reduces fever), and anti-inflammatory (reduces swelling) drug. Initially, this drug was used in human beings for various indications such as arthritis. The use of diclofenac was started in domestic animals in the region a decade ago. It was reported that the presence of diclofenac in the bodies of dead animals that had been treated with this drug shortly before death was harming the vultures feeding on contaminated carcasses (Oaks et al., 2004; Shultz et al., 2004; Swan et al., 2005).
The Department of Pharmacology and Toxicology, at the University of Veterinary and Animal Sciences, Lahore, has been given the task to investigate this problem. A series of experiments was conducted to study the likely causes of this problem and, if possible, find its solution by developing safer and efficacious alternatives to diclofenac for the treatment of animals. For this purpose, a chicken experimental model was developed to study the toxicity of diclofenac and other NSAIDs. These studies have shown that diclofenac produced similar toxic effects and mortalities in broiler chickens as had been reported from studies of diclofenac-poisoned vultures. Later on, therapeutic efficacy studies of safer alternative NSAIDs of diclofenac were conducted in horses, buffaloes.
On the basis of these current studies, it was concluded that diclofenac was toxic to chickens and no significant difference was present in the death rates in bird groups treated with toxic doses of diclofenac via oral and intramuscular routes. Sodium and potassium salts of diclofenac caused comparable casualties in broiler chickens (unpublished study). A number of other NSAIDs were screened for their toxicity profile using the chicken model. This study showed that phenylbutazone, dipyrone, meloxicam, piroxicam and ketoprofen were comparatively safer than diclofenac. However, phenylbutazone and dipyrone may not be appropriate alternatives for diclofenac in food-producing animals because they are known to cause a condition called agranulocytosis in human and animals. Agranulocytosis involves marked reductions in numbers of white blood cells that are responsible for maintaining the body's immunity against various diseases.
To evaluate the efficacy of safer drugs, fever was induced in buffalo calves with Escherichia coli endotoxin (lipopolysaccharide), and the animals were then treated them with ketoprofen, meloxicam orpiroxicam. Although, all three drugs were effective in lowering body temperature, ketoprofen was the most efficient. In another experiment, these drugs were used in the treatment of lameness in horses, and it was concluded that meloxicam was more effective followed by piroxicam and ketoprofen for the treatment of this particular problem.
Based on these observations, it is concluded that ketoprofen, meloxicam and piroxicam may prove quite safe drugs for the scavenging birds and may be used as safe alternatives to diclofenac in veterinary practice. It has been observed during this study that ketoprofen, piroxicam, and meloxicam are less toxic for broiler chickens and may prove better alternates to be used in place of diclofenac in animals. The use of these NSAIDs may be less toxic for scavenger birds. The commercial preparations of ketoprofen and meloxicam for veterinary use are available at least in two south-east Asian countries i.e. Pakistan and India. The prices of these NSAIDs are comparable with those of the veterinary preparations of diclofenac which were previously available in the region. On the basis of results of this study it is concluded that ketoprofen, piroxicam, and meloxicam are effective NSAIDs in domestic animals, hence may replace diclofenac in veterinary practice.

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